Relationships between caveolae and eNOS: everything in proximity and the proximity of everything

Abstract

Caveolae, flask-shaped invaginations of the plasma membrane occupying up to 30% of cell surface in capillaries, represent a predominant location of endothelial nitric oxide synthase (eNOS) in endothelial cells. The caveolar coat protein caveolin forms high-molecular-weight, Triton-insoluble complexes through oligomerization mediated by interactions between NH2-terminal residues 61-101. eNOS is targeted to caveolae by cotranslational N-myristoylation and posttranslational palmitoylation. Caveolin-1 coimmunoprecipitates with eNOS; interaction with eNOS occurs via the caveolin-1 scaffolding domain and appears to result in the inhibition of NOS activity. The inhibitory conformation of eNOS is reversed by the addition of excess Ca2+/calmodulin and by Akt-induced phosphorylation of eNOS. Here, we shall dissect the system using the classic paradigm of a reflex loop: 1) the action of afferent elements, such as fluid shear stress and its putative caveolar sensor, on caveolae; 2) the ways in which afferent signals may affect the central element, the activation of the eNOS-nitric oxide system; and 3) several resultant well-established and novel physiologically important effector mechanisms, i.e., vasorelaxation, angiogenesis, membrane fluidity, endothelial permeability, deterrance of inflammatory cells, and prevention of platelet aggregation.

Prostate-specific membrane antigen expression in regeneration and repair

“…1 Therefore, our findings of PSMA expression in endothelial cells associated with neovasculature may indicate that it is functioning to increase folic acid levels at the site of neovasculature formation, so that folic acid can exert its proangiogenic effects (Figure 4). In support of this, PSMA has been reported to coimmunoprecipitate with the caveolae marker, caveolin 1, 37 which also coimmunoprecipitates with eNOS, 38,39 suggesting the in vivo proximity of PSMA and eNOS.…”

Response of descending vasa recta to luminal pressure

“…Most error bars have been suppressed for clarity. microvessels to increase [Ca 2ϩ ] CYT (11,39,41), remodel (2,8,40), modulate permeability (24), and release NO (10,12,13,15) is firmly established. A single predominant mechanism through which endothelia sense and then respond to mechanical forces has not clearly emerged (1,8).…”

“…Integrins have been implicated in such mechanosensation. Of interest, ␤ 1 -integrins are associated with caveolae within which caveolin and signaling complexes regulate the activity of endothelial NO synthase (15,25,35,38). Direct or indirect activation of ion channel activity has also been implicated as an endothelial mechanosensor (1,3,8,16,18,19,43).…”

The role of nitric oxide in cancer

“…It should be noted that there are complicated signalling network(s) in endothelial cells capable of regulating eNOS activity. For example, the Akt-mediated phosphorylation activity can be enhanced by binding to heat shock protein-90 [30] and inhibited by binding to Caveolin-1 [31] [Fig 2].…”